Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants.
Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants.
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DOI：
10.1038/s41598-020-77717-4
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发表时间：
2020-11-26
影响因子：
4.6
通讯作者：
Vidal R
中科院分区：
文献类型：
--
作者：
Irimia-Dominguez J;Sun C;Li K;Muhoberac BB;Hallinan GI;Garringer HJ;Ghetti B;Jiang W;Vidal R
脑铁代谢异常在神经退行性疾病中的作用仍不清楚。在这里，我们调查神经退行性疾病遗传性铁蛋白病（HF）的分子基础，其中脑铁稳态失调是神经退行性疾病的主要原因。我们诱变铁蛋白的三重孔（3FP），即铁的主要进入途径，以研究铁蛋白的铁管理时，铁必须通过破坏的四重孔（4FP）产生的铁蛋白轻链（FtL）基因突变在HF中穿过蛋白质壳。我们使用冷冻电子显微镜和一系列体外功能分析来评估铁蛋白的结构和性质。3FP功能的丧失并没有改变铁蛋白的结构，但导致蛋白质溶解度和铁储存的减少。异常的4FPs作为替代路线的铁进入和退出的情况下，功能性3FPs，进一步降低铁蛋白铁储存能力。重要的是，即使是少量的MtFtL亚基也会显著损害铁蛋白的溶解性和功能，为HF患者中表达不同水平FtL的细胞类型中存在铁蛋白聚集体提供了理论基础。这些发现使我们讨论修饰孔是否可以用作HF的药理学靶点。
The role of abnormal brain iron metabolism in neurodegenerative diseases is still insufficiently understood. Here, we investigate the molecular basis of the neurodegenerative disease hereditary ferritinopathy (HF), in which dysregulation of brain iron homeostasis is the primary cause of neurodegeneration. We mutagenized ferritin’s three-fold pores (3FPs), i.e. the main entry route for iron, to investigate ferritin’s iron management when iron must traverse the protein shell through the disrupted four-fold pores (4FPs) generated by mutations in the ferritin light chain (FtL) gene in HF. We assessed the structure and properties of ferritins using cryo-electron microscopy and a range of functional analyses in vitro. Loss of 3FP function did not alter ferritin structure but led to a decrease in protein solubility and iron storage. Abnormal 4FPs acted as alternate routes for iron entry and exit in the absence of functional 3FPs, further reducing ferritin iron-storage capacity. Importantly, even a small number of MtFtL subunits significantly compromises ferritin solubility and function, providing a rationale for the presence of ferritin aggregates in cell types expressing different levels of FtLs in patients with HF. These findings led us to discuss whether modifying pores could be used as a pharmacological target in HF.
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影响因子：
13.3
作者：
Maulucci G;Chiarpotto M;Papi M;Samengo D;Pani G;De Spirito M
通讯作者：
De Spirito M
影响因子：
3.4
作者：
La, A.;Nguyen, T.;Linder, M. C.
通讯作者：
Linder, M. C.
影响因子：
4.8
作者：
Liu, Xiaofeng S.;Patterson, Leslie D.;Theil, Elizabeth C.
通讯作者：
Theil, Elizabeth C.
影响因子：
5.6
作者：
Sala, Davide;Ciambellotti, Silvia;Rosato, Antonio
通讯作者：
Rosato, Antonio
影响因子：
3
作者：
Suloway, C;Pulokas, J;Carragher, B
通讯作者：
Carragher, B